Aging and Alzheimer's disease (AD) are associated with an increase in oxidation of brain macromolecutes and impairment of signaling pathways critical for cell survival. The causative relationship between oxidation, disruption in signaling and neuronal dysfunction and death is currently only partially understood. The present application is based upon our observation that NFkB activation occurs rapidly during oxidative stress and this response is blocked by treatment with estrogens, both in vitro and in vivo. Additionally, we have observed that estrogens block the required step in activation of NFkB, phosphorylation of IkB. In the present application, we will attempt to address the role of NFkB in response to pro-oxidants by pursuing 5 specific aims. Aim 1 will assess the dose-, time- and estrogen receptor (ER)-dependence of the blockade of NFkB activation by estrogens. Aim 2 will define the protein kinases involved in pro-oxidant-induced phosphorylation of IkB and determine which of these many protein kinases that estrogens chronically dephosphorylate (e.g. ERKt/2, PKCepsilon, and others) are critical to IkB phosphorylation. Aims 3 will test the hypothesis that estrogens dephosphorytate a variety of protein kinases as well as other proteins critical to cell survival by activating phosphatases. Aim 4 will assess the role of NFkB activation in the deposition of Abeta in the brains of PS-1/APP over-expressing mice and determine if inhibition of NFkB activation by estrogens is responsible for the estrogen-induced reduction in Abeta in the brains of these mice. Finally, in Aim 5 we will characterize cognitive aging in female C57BL/6 mice, expose them to various ovarian steroid environments and assess the affects of age, cognitive decline and ovarian steroid on NFkB signaling. Collectively, these studies will address oxidative signaling in the brain during normal aging and AD and elucidate a mechanism by which estrogens can profoundly affect a variety of brain function disrupted in aging and AD.